This substance has the following formula: ##STR1##
It comes in the form of a powder or white crystals, is odorless, and has a melting point lying between 208.degree. C. and 212.degree. C. Diltiazem is known to inhibit the inflow of calcium through the special channels to be found in the membranes of a variety of cells. By this mechanism, it exerts a depressive effective on heart pacemaker activity and on auriculo-ventricular node conduction resulting in a negative chronotropic effect. Diltiazem appears to have a weak negative inotropic effect on the heart muscle and it gives rise to vasodilatation of smooth muscle. Diltiazem reduces intra-cellular sodium by stimulating the sodium-potassium pump of smooth muscle cells and of other types of cell. This effect is responsible for membrane stabilizing effects and for its diuretic (non-vascular) action on renal tubules. Clinically, Diltiazem is used above all as an anti-angina remedy, both against chronic stable angina and against unstable angina. It also has activity against arythmia and may be used in other cardiovascular complaints such as congestive cardiac insufficiency and Raynaud's syndrome, and also in peripheral and cerebral circulatory insufficiency.
Diltiazem is also under close study for hypertension, and is already an indication recognized by the authorities in many countries.
It is a substance which has few side effects, in particular when compared with other calcium antagonistic substances such as Nifedipine or Verapamil, and it can thus be considered for use in long-term treatment.
At present, Diltiazem is used in the form of immediate-release pills having doses of 30 mg, 60 mg, and 90 mg. Recommended dosage is 180 mg taken two or three times a day, up to 240 mg or even 360 mg in severe cases.
The literature shows that Diltiazem is absorbed very rapidly and that its concentration peak is reached between three and a quarter hours and four hours. Its half life is four hours to seven hours. The phenonemon of saturation to therapeutic doses is not observed, and consequently the medicine does not accumulate after repeated administration. Tolerance to Diltiazem is very good. Considerable variability has been observed in the pharmacokinetic parameters of different subjects, which makes it difficult to maintain plasma concentration in the therapeutic window. This information, together with experience acquired while developing numerous products, has led the Applicant to attempt to optimize the currently existing Galenical preparation of Diltiazem by selecting a sustained- or slow-release preparation in the form of capsules, pills, or sachets containing microgranules.
The slow-release preparation should reduce the number of times the medicine is taken per day by extending the time over which the substance is released so as to enable the medicine to be taken, if possible once a day, or at most twice a day. Thus, in order to improve patient comfort, by avoiding too many occasions in the day when the medicine needs to be taken (with the attendent risk of wrong dosage), and also to reduce the risk of undesirable effects related to very high concentration peaks in the blood, the present invention seeks to maintain the blood concentration in an equilibrium state having a minimum of 40 ng/l and a maximum that does not exceed 300 ng/ml. This result cannot be obtained by taking the usual preparations or types of immediate action pill or delayed action pill as commercially available in Europe only once or twice a day, since the available pills and preparations do not make it possible to remain within the above-specified blood concentration limits. In addition, the selected microgranular form of preparation improves dispersion of the active substance. After the capsule opens, the microgranules spread widely through the digestive tract and increase the contact area between the active substance and digestive liquids, thereby ensuring good distribution of the medicinal effect by improving absorption. Further, by splitting up the unit dose into minute fractions, it is impossible for a high concentration of active substance to build up at a given point in the digestive tract, and this serves to reduce local intolerance and also to reduce intra- and inter-patient variations.
Prior art attempts have been made to prepare Diltiazem in the form of microgranules. Thus, European patent application number 0 149 920 filed in the Name of Elan Corporation plc describes microgranules containing Diltiazem in association with an organic acid and a lubricant inside an outer membrane (as defined by United States Phamacopea No. 21, or USP No. 21 for short) which does not make it possible to obtain satisfactory concentrations in the blood flow (i.e. not less than 40 ng/ml) without the appearance of unwanted side effects when taken only once or twice a day for daily doses lying in the range 100 mg to 500 mg, and preferably in the range 150 mg to 400 mg. Further, the stability of such microgranules can be affected by the presence of organic acids which may have an influence on the physiochemical characteristics of the outer or inner membranes coating the microgranules.